Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein

Mutations in bbs6 cause two clinically distinct syndromes,bardet-biedl syndrome (bbs),a syndrome caused by defects in cilia transport and function,as well as mckusick-kaufman syndrome,a genetic disorder characterized by congenital heart defects. congenital heart defects are rare in bbs,and mckusick-kaufman syndrome patients do not develop retinitis pigmentosa. therefore,the mckusick-kaufman syndrome allele may highlight cellular functions of bbs6 distinct from the presently understood functions in the cilia. in support,we find that the mckusick-kaufman syndrome disease-associated allele,bbs6h84y; a242s,maintains cilia function. we demonstrate that bbs6 is actively transported between the cytoplasm and nucleus,and that bbs6h84y; a242s,is defective in this transport. we developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of bbs6,and we find interaction with the swi/snf chromatin remodeling protein smarcc1a (smarcc1 in humans). we demonstrate that through this interaction,bbs6 modulates the sub-cellular localization of smarcc1 and find,by transcriptional profiling,similar transcriptional changes following smarcc1a and bbs6 manipulation. our work identifies a new function for bbs6 in nuclear-cytoplasmic transport,and provides insight into the disease mechanism underlying the congenital heart defects in mckusick-kaufman syndrome patients. © 2017 scott et al.